The present technology relates to nucleic acids and encoded polypeptides which are expressed in cancers. The present technology also relates to agents which bind the polypeptides. The nucleic acids, polypeptides coded for by such nucleic acids and peptides derived therefrom, as well as related antibodies and cytolytic T lymphocytes, are useful, inter alia, in diagnostic and therapeutic contexts.
Despite interdisciplinary approaches and exhaustive use of classical therapeutic procedures, cancers are still among the leading causes of death.
More recent therapeutic concepts in cancer therapy aim at incorporating the patient's immune system into the overall therapeutic concept by using recombinant tumor vaccines and other specific measures such as antibody therapy. A prerequisite for the success of such a strategy is the recognition of tumor-specific or tumor-associated antigens or epitopes by the patient's immune system whose effector functions are to be interventionally enhanced.
Tumor cells biologically differ substantially from their nonmalignant cells of origin. These differences are due to genetic alterations acquired during tumor development and result, inter alia, also in the formation of qualitatively or quantitatively altered molecular structures in the cancer cells. Tumor-associated structures of this kind which are recognized by the specific immune system of the tumor-harboring host are referred to as tumor-associated antigens.
The specific recognition of tumor-associated antigens involves cellular and humoral mechanisms which are two functionally interconnected units: CD4+ and CD8+ T lymphocytes recognize the processed antigens presented on the molecules of the MHC (major histocompatibility complex) classes II and I, respectively, while B lymphocytes produce circulating antibody molecules which bind directly to unprocessed antigens. The potential clinical-therapeutical importance of tumor-associated antigens results from the fact that the recognition of antigens on neoplastic cells by the immune system leads to the initiation of cytotoxic effector mechanisms and, in the presence of T helper cells, can cause elimination of the cancer cells (Pardoll, Nat. Med. 4:525-31, 1998).
Antibody based cancer therapies have been successfully introduced into the clinic and have emerged as the most promising therapeutics in oncology over the last decade. Eight antibodies have been approved for treatment of neoplastic diseases, most of them, however in lymphoma and leukemia (Adams G P, Weiner L M, Nat Biotechnol 23:1147-57, 2005).
One of the challenges to be mastered for the advent of the next generation of upgraded antibody-based cancer therapeutics is the selection of appropriate target molecules, which is the key for a favorable toxicity/efficacy profile.
The search for genes tightly silenced in the vast majority of healthy tissues moves into the focus of attention the intriguing observation that genes of the gametogenic and/or trophoblastic lineage are frequently ectopically activated and robustly expressed in human cancer. Based on phenotypical similarities between germ cells, pregnancy trophoblast and cancer cells, John Beard proposed as much as 100 years ago a “trophoblastic theory of cancer” (Beard J, Lancet 1:1758-63, 1902; Gurchot C, Oncology 31:310-3, 1975). The discovery of the sporadic production of chorionic gonadotropin, alpha-fetoprotein, CEA and other trophoblastic hormones by cancer cells provided the first molecules shared between neoplastic and trophoblastic cells (Acevedo H F et al., Cancer 76:1467-75, 1995; Dirnhofer S et al., Hum Pathol 29:377-82, 1998; Gurchot C, Oncology 31:310-3, 1975; Iles R K, Chard T, J Urol 145:453-8, 1991; Laurence D J, Neville A M, Br J Cancer 26:335-55, 1972). The concept was reignited by the inauguration of the steadily growing so-called cancer/germline (CG) class of genes, which represents more than 100 members, each expressed in a variety of tumor types. The observation that entire trophoblastic and gametogenic programs escape transcriptional silencing and are ectopically activated in cancer cells (Koslowski M et al., Cancer Res 64:5988-93, 2004; Simpson A J et al., Nat Rev Cancer 5:615-25, 2005) indicates that within this class of genes with exquisitely selective tissue distribution, appropriate targets for mAB therapy may be found.
It was the object of the present technology to provide target structures for a diagnosis and therapy of cancers. This object is achieved by the subject matter of the claims.